A variety of human and experimental neurologic diseases are characterized by the accumulation of normal-appearing 100 angstrom units neurofilaments to accumulate are not understood. To gain insight into these mechanisms we have begun studies of the role of axonal transprot in neurofilamentous pathology, using a simple, reproducible model, B,B-iminodipropionitrile (IDPN) intoxication in the rat. This agent produces massive neurofilamentous axonal swellngs in the very proximal region of motor axons. Our initial studies of the transport kinetics and gel fluoroautoradiography show that IDPN prevents transport of the major slow component peak, containing predominantly neurofilaments, without significant effects on fast axonal transport. One consequence of this selective impairment of slow transport is atrophy of the axon distal to the filamentous swellings. On the basis of these initial studies of IDPN, we propose a detailed study, focusing on four objectives. First, we will systematically define the effect of IDPN on slow transport, including the tie course, reversibility, and specificity with regard to proteins transported abnormally. Second, we will document the pathologic consequences of accumulation of the slow component (in the distal axon). Third, we will examine the effect of impaired slow transport, particularly of neurofilaments, on axonal regeneration and maturation following a nerve crush. Finally, the approach developed in these studies will be extended to other models of neurofilamentous pathology, particularly hereditary canine spinal muscular atrophy. This disease, a model of motor neuron disease, has an axonal pathology very similar to that of IDPN intoxication. Since the clinical and pathologic features of this disease resemble those documented in human motor neuron disease, we anticipate that axonal transport studies in this model will be relevant to the pathogenesis of motor neuron degeneration.